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Introduction: The adversities of aging
Ageing Research Reviews 5 (2006) 221–238 www.elsevier.com/locate/arr
Review
Introduction: The adversities of aging Roy G. Cutler *, Mark P. Mattson Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA Received 5 February 2006; accepted 16 May 2006
Abstract The aging process is evolutionarily conserved and subject to quantitative modification by both genetic and environmental factors. Fundamental mechanisms of aging result in progressive deficits in the function of cells and organs, often leading to diseases that ultimately kill the organism such as cancers, cardiovascular disease and neurodegenerative disorders. Oxidative stress and damage to all of the major classes of molecules in cells are involved in aging and age-related diseases. The widely pursued approach of targeting disease-specific processes to develop therapeutic interventions has not had a major impact on healthspan. A more productive approach would be to target the fundamental mechanisms of aging throughout adult life so as to extend healthspan. Caloric restriction and regular exercise are two such approaches. Published by Elsevier Ireland Ltd. Keywords: Aging process; Oxidative stress; Healthspan
1. Aging is our #1 health problem Aging is the leading cause of disability and death in the United States and other developed countries. The 2003 CDC National Vital Statistics Report shows that about 85% of all deaths are caused by age-related diseases (Table 1; Fig. 1; CDC, National Vital Statistic Reports, 2006a). 2. The degenerative effects of aging are universal What we call aging is the noticeable loss of function and the onset of the degenerative diseases that is caused by the aging process. Many scientists and physicians define aging as * Corresponding author. E-mail address: [email protected] (R.G. Cutler). 1568-1637/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.arr.2006.05.002
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Table 1 The top 15 causes of death as reported by the CDC, National Vital Statistics for U.S. 2003 (raw data was obtained from CDC, National Vital Statistics Reports, 2006a) Cause of death Heart disease Cancer Stroke Pulmonary diseases Accidents Diabetes Pneumonia and influenza Alzheimer’s disease Nephritis (kidney) Septicemia (infection) Suicide Liver disease Hypertension Parkinson’s disease Homicide Other Total
Number of deaths in 2003 685089 556902 157689 126382 109277 74219 65163 63457 42453 34069 31484 27503 21940 17997 17732 416932 2448288
the loss of a cell/organ/organisms peak function that continues until its failure and death. In humans most physiological functions such as hearing, eyesight, taste, lung capacity, agility, immune response, adaptation to change, etc., reach peak ability between the ages of 11 and 20 years old. After that age there is a slow decline in performance as the degenerative process of aging begins (Bafitis and Sargent, 1977). The rate of the degenerative effects of aging is different for each cell/organ/organism due to genetics and environmental exposure. Most of us will not reach our species maximum lifespan potential due to the inheritance of genes that predisposes to an accelerated onset and/or progression of a
Fig. 1. Age is the greatest risk factor for developing degenerative diseases. The number of deaths from the top three causes in the U.S. for 2003 vs. age for the total population (raw data was obtained from CDC, National Vital Statistics Reports, 2006a).
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Table 2 Common age-related degenerative diseases and functional deficits (data obtained from Kohn, 1982; Maynard, 1966) List of common age-related degenerative process and functional deficits Loss of stem cell population Loss of hormone regulation Male patterned baldness Female menopause Sarcopenia (i.e. muscle weakness, frailty) Osteoporosis Graying hair Loss of insulin sensitivity Type II diabetes (insulin insensitive) Cancer Arteriosclerosis, heart disease, stroke Cataracts Hearing loss Incontinence Metabolic disturbances Osteoarthritis and rheumatoid arthritis Hypertension Loss of skin elasticity and collagen (i.e. wrinkles, liver spots, thinning) Retinal degenerative diseases (i.e. macular degeneration, retinitis pigmentosa) Lipofuscin and protein aggregates: ALS (SOD1), Alzheimer’s (Abeta), Parkinson’s (alpha-synucle in) Dementia Increase hair growth, density and root thickness in nose, ears, beard, chest, back, pubic, eye brows
particular age-related disease, and/or due to our environmental exposure to harmful agents that promote an age-related disease. If we are genetically and environmentally lucky, we can live to, or near, our species maximum lifespan potential, which is around 122 years old. However, the degenerative effect of aging is, in general, uniform for every cell/organ/ organism. Even though an elderly person has not died earlier from a genetic or environmentally induced weak link in their vital life processes, their bodies are still showing signs of the degenerative effects of aging. A good example to further illustrate that the degenerative effects of aging are universal is to look at a person that is over 100 years of age. They have not yet died of a particular disease, but they do have signs of degeneration and loss of function throughout their body such as loss of: hearing, hormone regulation, skin elasticity, taste, vision, memory, immune responsiveness, etc., that impairs their productivity and quality of life (Table 2; Fig. 2; Kohn, 1982; Maynard, 1966).
3. How much of an increase in quality of life and productivity can we expect from curing one ailment? It has been estimated that if we were able to completely eliminate and cure all forms of cancer the impact on healthspan and lifespan in the United States would only increase by an average of 2.3 years (National Center of Health Statistics. USPHS & U.S. Bureau of the Census, 1973; Tsai et al., 1978). The reason for this is that most people who suffer from major
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Fig. 2. (a) Self-accessed decrease of function and quality of life with age; (b) Clinically diagnosed disease or chronic health ailment causing limitation of activity (raw data for both figures were obtained from a CDC National Health Interview Survey conducted on 100,000 people across the U.S. from 2002–03(CDC, NCHS. Review Health, United States, 2005 Tables. http://www.cdc.gov/nchs/data/hus/hus05.pdf Health United States, Figs. 19 and 20). Surveys where sent to 358 primary sampling units (PSUs) drawn from approximately 1900 geographically defined PSUs that cover the 50 states and the District of Columbia.
killer diseases are over 65 years old and would soon be dying from another failing vital function (Table 3; Fig. 1). The elimination of fatal diseases such as coronary heart disease and cancer acts to increase the proportion of years with disability and healthcare costs because of the medical expenses during the added years of life. In contrast, not treating fatal diseases while eliminating disabling diseases like arthritis and osteoporosis acts to shorten lifespan, but with fewer years of disability (Nusselder et al., 1996; Bonneux et al., 1998).
4. Ages of peak performance and productivity The adverse effects of aging can clearly be seen in the quickly declining peak physical performance of athletes. For example, the average age of world record holding athletes
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Table 3 The potential gain in years of life expectancy if major causes of death were eliminated (raw data was obtained from USPHS, 1973; Tsai et al., 1978) Expectancy of Life gained at birth and age 65 years due to elimination of various causes of death Cause of death
Gain in expectancy of life (years) if cause was eliminated At birth
At 65 years old
Cardiovascular disease Heart disease Stroke Cancer Accidents (not motor vehicle) Motor vehicle accidents Influenza and pneumonia Infectious disease Diabetes
10.9 5.9 1.3 2.3 0.6 0.6 0.5 0.2 0.2
10.0 4.9 1.2 1.2 0.1 0.1 0.2 0.1 0.2
whose sport requires balance and explosive strength is 13–20 years old, whereas skilled sports such as tennis and golf peak at 24 and 31 years, respectively (Table 4; Kaga and Tanaka, 1980; Schulz and Curnow, 1988; Schulz et al., 1994; Baker et al., 2003; Anton et al., 2004; Nakamura et al., 1998). Animals that live in an environment where mortality from predation is high have evolved genetic programs for quick development and breeding that needs to be balanced with high fitness (e.g. gazelles on the plains of the African savanna being pursued by lions, tigers and cheetahs). The animals that are at the highest risk for being caught by a predator are the newborn and the middle-aged. You will rarely ever see any adverse signs of aging in either the predator or prey in these types of animal populations because top mental and Table 4 Peak ages for physiological performance as clinical norms for humans (gender and race averaged, then rounded to nearest whole value) Peak ages of physiological performance Hearing peaks at 5 years old Smell peaks at 10 years old Taste peaks at 10 years old Flexibility and balance peaks at 13 years old Muscle strength peaks at 18 years old Tissue repair peaks at 13 years old Short term memory peaks at 20 years old Creativity peaks at 4–6 years old Immune response peaks at 13 years old Lung capacity peaks at 20 years old Creativity data was highly variable and best expressed in a range. Flexibility, tissue repair capacity and immune response all peaked right before puberty, after which there was a sharp decline due to sex steroids. There was a notable difference between the peak lung capacity of female (17 years) and males (21 years) because of the 3.5year extension of bone growth in males. Peak height for females is 17 years and males is 21 years of age (Kaga and Tanaka, 1980; Schulz and Curnow, 1988; Schulz et al., 1994; Nakamura et al., 1998; Baker et al., 2003; Anton et al., 2004).
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physical performance (e.g. eye sight, hearing, explosive fast twitch muscle strength) are needed daily to survive (Ansved et al., 1991). A measurement of the age-related decline in functional performance as biomarkers of aging has been pioneered by sports physiologists such as Richard Hochschild for which he has developed the H-SCAN. This computer-based test connects with the provided headphones, lung peak flow meters, and other calibrated measuring devices to calculate the functional status of the subject and their estimated physiological age based on 12 tests (Hochschild, 1990). The tests include: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)
auditory reaction time; highest audible pitch; vibro-tactile sensitivity; visual reaction time; muscle movement time; lung: forced vital capacity; lung: forced expiratory volume, 1 s; decision reaction time; decision movement time; memory; alternate button tapping; visual accommodation (i.e. eye lens flexibility).
Pulmonary, cardio and exercise physiologists were the first to develop and standardize vital functional tests as biomarkers to determine a subject’s health status (e.g. tread mill stress test to determine VO2 max (maximum oxygen uptake) and maximum heart rate) to maximize an athlete’s performance (Fig. 3; http://www.americanheart.org/presenter.jhtml?identifier=4736; Cooper et al., 1992).
Fig. 3. Decrease of lung function (vital oxygen capacity, VO2 max) with age (raw data was obtained from Cooper et al., 1992), and decrease of heart function capacity (maximum heart rate) with age (raw data was obtained from the American Heart Organization website, http://www.americanheart.org/presenter.jhtml?identifier=4736).
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5. The evolution of lifespan ‘‘Nothing in biology makes sense except in the light of evolution’’: Theodosius Dobzhansky, geneticist (1900–1975). Most evolutionary scientists believe that humans evolved from the great apes with enhanced brain size, convolutions, and perpetual neoteny (i.e. curious, high ability to learn). These traits allowed humans to develop the key survival strategies of tool development, language, socialization, trans-generational information transfer, and migration to better adapt and control our environment. In order to get the largest brain through the mother’s birth canal human infants are born unusually immature and helpless relative to other species (Leigh and Park, 1998). One hypothesis of human evolution is that many of the genes that helped contribute to increased brain size also played roles in slowing fetal development rate. Humans are unique in that we are born with a very premature brain that keeps on growing after birth. A key difference between chimpanzee and human brains is that after birth the human brain continues to grow dramatically during the first postnatal year. About one-ninth of a newborn human baby’s weight is its brain. However, by the time a person reaches adulthood their brain only makes up 1/50th of their total body weight. In most species other than human, the number of neurons in their developing brain is fixed prior to birth. Human neonatal brain development and overall development seems to have been slowed down by changes in gene expression via an environmental selection for a larger adult brain. This slow down in development also has the advantage of extending key learning periods, or windows of opportunity, which gives children the exceptional abilities to learn language, tool usage and problem solving. These skills take time and often involve training during certain seasons, and necessitates a delay in sexual reproduction. We believe that during the evolution of man there was a strong environmental pressure for the selection of genes that slowed development rate by reducing the accumulation or signaling of key growth-regulating hormones. The lowering of such developmental hormones not only resulted in lengthening the time periods for brain growth and development, but also proportionally extended healthy years and maximum lifespan (Cutler and Semsei, 1989).
6. Are development and aging rates both determined by the same master genes and hormones? There is a strong correlation between a species maximum lifespan and its developmental rate, which suggests that these processes share a common mechanism that is species specific and genetically programmed (Cutler and Semsei, 1989; Bains et al., 1997). For example, the genetic code between chimpanzees and human is about 98% the same; however, the maximum potential lifespan for the chimpanzee is 56 years whereas for humans it is 122 years. This correlation suggests that the differences that determine the timing of developmental stages (e.g. puberty, brain maturation) and physiological aging rate (i.e. maximum lifespan potential) may be due to the expression of a very small number of genes. Work by de Magalha˜es and Sandberg
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Fig. 4. (a) Changes in synaptic plasticity and cognitive function with age; (b) changes in the total number of neurons and synapses across a lifespan (raw data was obtained from de Magalha˜es and Sandberg, 2005).
(2005) has shown that synaptic plasticity and cognitive function peak around the time of puberty and are maintained proportional to a species maximum lifespan potential. They propose that the same mechanisms that shape the adult phenotype continue at later ages contributing to cognitive dysfunction and eventually dementia (Fig. 4a and b). In general, the physiological aging rate of a cell/organ/organism/species can be defined by its maximum lifespan. In other words, physiological aging rate is directly related and relative to a species developmental rate and maximum lifespan potential. For example, one of the ways researchers have genetically selected for long-lived Drosophila melanogaster is to pick the ones that are last to sexually mature (Rose et al., 1992). Transgenic experiments also indicate that a reduction in certain growth factors can slow down developmental events while increasing health and extending maximum lifespan. Finally, a well-known characteristic of calorie-restricted mice/rats is the lower growth factors and delayed development, which includes reaching puberty (and the onset of menopause in females) later. The delay of developmental events by calorie restriction also occurs in monkeys and humans (Park et al., 1994; Holehan and Merry, 1985).
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Table 5 Genetically modified gene indicated by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB name), functional change (i.e. / double chromosome knockout, ++/++ over expression of gene) and note on catalytic function Gene changed
Extension of maximum life span (%)
Species
p66shc / (apoptosis, phenoptosis) PROP1 / (GH, prolactin orTSH) GHR/BP / (GH receptor binding protein)
30 50 50
Mouse (Migliaccio et al., 1999) Mouse (Bartke et al., 1998) Mouse (Coschigano et al., 2000)
Cu/ZnSOD ++/++ (in motorneurons) MnSOD ++/++ (in motorneurons) mth / (putative G-protein-coupled receptor) indy / (sodium dicarboxylate cotransporter)
40 30 35
Drosophila (Parkes et al., 1998) Drosophila (Phillips et al., 2000) Drosophila (Schmidt et al., 2000)
45
Drosophila (Rogia et al., 2000)
age-1 / (PI3 kinase homologue) daf 2 / (insulin receptor homologue) clk-1 / (CoQ biosynthesis homologue) spe-10 / (unknown) spe-26 / (unknown) old-1 / (putative receptor tyrosine kinase)
65 100
C. elegans (Johnson et al., 2000) C. elegans (Kenyon et al., 1993)
40
C. elegans (Wong et al., 1995)
40 65 65
C. elegans (Cypser and Johnson, 1999) C. elegans (Lithgow et al., 1995) C. elegans (Rikke et al., 2000)
7. Evidence that individual genes regulate lifespan Humans live about two times longer than our nearest relatives, the chimpanzee and bonobo. Humans also have an unusually long span of healthy and productive years of life relative to most other species. So what makes humans live long and healthy lives? Research indicates the existence of ‘‘longevity determinant genes’’ (Cutler et al., 2005; Vijg and Suh, 2005). Genetic analyses of human lineages with exceptional longevity have honed in on specific regions of the genome (e.g. chromosome 4) (Perls and Terry, 2003). However, only a few specific longevity-related genes have been identified. For example, a recent study of Ashkenazi Jewish centenarians in which 36 different genes related to cardiovascular disease were analyzed demonstrated a strong correlation of a polymorphism in the apolipoprotein C3 gene promoter with longevity (Atzmon et al., 2006). While progress in identifying genes that regulate longevity in humans has been slow, numerous such genes have been identified in lower organisms. The genes listed in Table 5 have been shown to affect the maximum lifespan of mice, flies and, providing evidence that individual genes can have a big impact on increasing the lifespan and health span of a species. What most of these genes have in common is that they relate to oxidative stress and developmental growth factors such as insulin and IGF-1. Oxidative damage has been shown to play a key role in the onset and progression of age-related diseases, and therapies to reduce oxidative stress often help to slow down the disease process and maintain good health.
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8. Can aging be slowed? Calorie restriction can increase the lifespan of rodents by up to 40%, which is accompanied by a proportional extension of healthspan (Weindruch and Sohal, 1997). Calorie restriction has been shown to slow the onset and progression of age-related degeneration of tissues throughout the body including collagen cross linking, accumulation of lipofuscin, lipid droplets, sarcopenia, cataracts, cognitive decline, kidney disease, arthritis and cancer. The magnitude of the life-extending effect of calorie restriction depends upon the energy intake of the control group and the amount by which calories are reduced below the control level. In most studies of mice and rats the control group are fed ad libitum and equivalent to overfed obese humans. However, if nutritional requirements are maintained, then the progressive reduction in calorie intake continues to extend lifespan until near the point of starvation. Studies of non-human primates (Roth et al., 2004) and of humans (Heilbronn et al., 2006) suggest that calorie restriction will also extend lifespan in humans. Two major hypotheses of the root cause of aging: (1) Accumulation of damaged molecules—which includes the free radical hypothesis of aging, was first developed by Harman in 1957 and today is the most popular hypothesis among gerontologists (Harman and Harman, 2003). Examples of oxidative damage include oxidized proteins, protein aggregates (e.g. amyloid beta peptide in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease), lipofuscin, lipid peroxides (e.g. 4hydroxy-nonenal, 8-epi-prostaglandin F2alpha), oxidized DNA adducts (e.g. 8hydroxy-2-deoxy-guanosine) and glycation products (Terman, 2001). This hypothesis also includes the idea that the accumulation of (oxidatively induced) DNA mutations results in aberrant gene expression, defective proteins and increased incidence of cancer and cell death. However, recent data in mice indicate that the qualitative and quantitative nature of DNA damage and repair does not change significantly with age (Hill et al., 2005). However, there is considerable evidence supporting a role for the accumulation of mitochondrial DNA deletions with aging and oxidative stress, particularly in postmitotic cells such as neurons and myocytes (Kraytsberg et al., 2006). (2) Antagonistic pleiotropy—first developed by G.C. Williams in 1957, which states that a gene or gene product that is responsible for positive effects when young, later causes the detrimental effects of aging (Rose and Charlesworth, 1980). Since most species in the wild are killed by environmental hazards before they become old, negative pleiotropic genes would not be evolutionarily selected for. One example of a possible antagonistic pleiotropy mechanism is the accumulation of sterols and steroids to toxic levels during aging (e.g. cholesterol in cardiovascular foam cells, estrogens in precancerous breast and prostate cells) (Huber et al., 2002; Bellosta et al., 2000).
9. What can we do about aging now? (1) Limit calories to maintain a healthy mass index (BMI). Many health experts would also suggest fasting with plenty of water. The length and frequency of fasting should be individualized to a regimen makes you feel healthy.
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(2) Exercise—the current Department of Health and Human Services, USDA recommendation is 60 min of exercise three to four times per week (USDA, Dietary Guidelines, 2005). Exercising in the morning before eating is a popular way to rev-up the metabolic system, increasing fat catabolism and decreasing glucose levels similar to that which occurs during a 24 h fast. In fact, studies have shown that 20 min of morning (or 4 h fast) exercise has the same fat burning effect as 60 min after food intake (Bergman and Brooks, 1999; McCarty, 1995). Exercise has also been shown be a stressor that acts to induce phase II detoxification, a mechanism much like that suggested for the beneficial dietary effects of phytochemicals in fruits and vegetables (Duncan et al., 1997). (3) Eat fruits and vegetables—the USDA recommends eating five servings of fruits and vegetables per day (USDA, Dietary Guidelines, 2005). The health benefits of fruits and vegetables are not the same; there are some that have been classified by many as ‘‘super foods’’. These include the brassica, or cruciferous, family of vegetables, which includes cabbage, broccoli and broccoli sprouts (which contain sulforaphane), cauliflower, bok choy and horseradish (which contain 6-methylsulfinyhexyl isothiocyanate). Also on the list of ‘‘super foods’’ are brussel sprouts, spinach, kale, carrots and blueberries. Epidemiology studies have shown that people who frequently eat broccoli had much lower incidences of many types of cancer and Alzheimer’s disease (http://www.alzinfo.org/news/NewsArticle7-29-2004-11-38-AM.aspx; http:// www.alzinfo.org/news/NewsArticle8-18-2005-1-35-PM.aspx; Michaud et al., 1999). The mechanism by which broccoli benefits health does not seem to be by the antioxidants as previously thought, but by the natural poisons (i.e. insecticides) used by the plant to ward off insects. These compounds like sulforaphane in broccoli and terpenoids in citrus oils activate the phase II pathway that conjugates the poison and removes it from the body. The healthy aspect of this process is that while getting rid of the food poisons the revved-up phase II conjugation mechanism also cleans up other harmful metabolic byproducts like oxidized steroids and lipid peroxides. Phenolic antioxidants like tocopherol (i.e. Vitamin E), carotenoids, and many dietary spices (e.g. curcumin, black pepper, brown mustard), also activate this pathway and so the biggest benefit in dietary phytochemicals may not be in trapping free radicals but in activating the phase II conjugation mechanism (Gao and Talalay, 2004). (4) Clean environment—limit chronic exposure to toxins and carcinogens like tobacco smoke, alcohol and radon. (5) Optimize stress—as with most biological processes, the amount of stress, rest and sleep required for optimal health follows a bell curve; too little or too much are bad for long term health. Studies have shown that the longest lived people get between 7 and 8 h of sleep per night and subject themselves to moderate daily de-stressors including exercise and social interactions (Kripke et al., 2002; Patel et al., 2004).
10. How would slowing aging affect our population? Many people believe that by slowing the degenerative aging process we would have too many physiologically old people, a social security crisis and in general more problems than it is worth. In reality, we would have more physiologically younger people who have a
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higher productivity because of an increased number of years working at peak physiological performance. Providing that the birth rate is low, the end result would be a higher percentage of the population would stay in the work force longer. People would have the ability and drive to work for many years longer, personal income and savings would increase and the overall national economy would flourish. As America and most industrial nations working population ages, the percent of disabled and retired people go up which puts an economic strain on the current working population and governments. On its current path, the United States Medicare program is estimated to go bankrupt by the year 2019 and Social Security by 2042 (Gundling, 2001; CEA, 2005). Trying to cure or treat the symptoms of each age-related disease separately as if they were unrelated to one another has not had a major impact on quality of life and productivity (Tables 2 and 3). The current piece meal approach to healthcare also seems to be exacerbating our economic problems by utilizing expensive temporary patches (e.g. drugs and surgery) that result in a minor slowing of disease processes and prolongation of the period of morbidity. This strategy usually does not result in returning people back to the workforce and is not cost effective for the individual, retirement programs, health care programs or the government. However, there is little incentive to institute anti-aging interventions that would increase healthspan because the current system of geriatric medicine is a major profitable market for physicians and pharmaceutical companies.
11. What about the economics of slowing aging? Overpopulation could be a potential problem because of the extension of childbearing years. However, one factor that may play a big roll in circumventing this potential problem is that the majority of the people who are interested in voluntarily enhancing their health and longevity are usually well educated and tend to have small families (Marshall and Marshall, 1982). Many developed nations populations have been shrinking due to having less children. The number of people 65 years and older in many developed countries such as Italy, Germany and Japan is currently up to 20%, and estimated to be near 35% by 2050. The elderly dependency ratio in Japan is expected to go up to 71 retired per 100 working age people by 2050 compared to the current ratio of 54.3/100 (US 2006 elderly dependency ratio is 35.3) (http://www.census.gov/ipc/www/idbagg.html) (Ishibashi, 1998). The decline in the working population is expected to cause age-related economic recessions throughout the world, which will put greater pressure on employee efficiency, automation and demand for energy (e.g. petroleum). The cost of decreased job performance do to degenerative aging is substantial. This can particularly be seen in the short career spans of athletes (Young and Starkes, 2005). Just a minor weakening of eyesight, hearing or slower reaction time can cost athletes the game and increases risk of injury (Schulz et al., 1994; Barry and McGuire, 1996). The effects of aging on the functional performance in the US workforce can be seen in the changes in productivity and working hours; note that peak employment productivity closely follows the general peaks of physiological functions during our lifespan (Fig. 5; CDC National Center for Health Statistics, 2006b). From 1950 to 2004 healthcare expenditures in the United State rose 300%, while the population only increased by 200% (http://www.cdc.gov/nchs/data/hus/hus05.pdf#091).
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Fig. 5. (a) Age of peak employment productivity (hours worked/week) and age of peak physiological function as measured by vital lung capacity; (b) average number of deaths per 100k employed workers during 1994–2001 (raw data was obtained from CDC United States Health 2005 report. www.cdc.gov/nchs/data/hus/hus05.pdf).
This increase was largely due to the 9% increase in our aging population. Over 87% of healthcare and pharmaceutical costs come from people over 45 years old (http:// www.cdc.gov/nchs/data/hus/hus05.pdf#091). It is estimated that by 2050 the population of people 65 years and over will rise 240%, from 7.6% (2004) to 18.3% (2050). Unless changes are made the predicted 2050 healthcare expenditure will be about 25% of the gross national product (CDC National Center for Health Statistics, 2005).
12. What about our quality of life? Increasing healthy years of life acts to increase our environmental hazards, which could hypothetically be extended to a point where we are more likely to die from an accident rather than wasting away in a nursing home. Extending the years of peak function,
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performance, and productivity will not only add to our own personal enjoyment of life but will also significantly add to the wealth of our economy.
13. Feasible goals A few gerontologists like Robert Butler have set a target of increasing average healthspan by 7 years. This goal was chosen because the exponential rise of onset and progression of age-related diseases doubles approximately every 7 years. Extending our lifespan by 7 years would result in cutting in half the incidence and prevalence of frailty, disability and risk of major causes of morbidity and mortality across the board (Butler and Brody, 1995; Butler, 2004).
14. A milligram of prevention is worth a kilogram of cure: a call to action By the time a patient is symptomatic and clinically diagnosed with an age-related disease the damage has already been done. All age-related diseases progress slowly such that the patient has usually experienced years of progressive loss of function, loss of work performance and quality of life. Once the damage is done going back to try to repair it is in most cases currently impossible. Recently, gerontologists have been focusing their research program goals toward ‘‘successful aging’’, ‘‘healthy aging’’ or ‘‘aging gracefully’’. We feel that this terminology is off the mark and may even misdirect research efforts away from trying to find the root cause of the problem to just reacting to the many symptoms related to aging. Instead, the answer to increasing healthspan lies in prevention by understanding the root causes of aging and holistically slowing down the aging process thereby delaying the loss of performance, degeneration and disease. The result would be an increase of healthy and productive years. Each species has a tightly controlled development and maturation rate that fits with their life cycle. The driving force for unusual longevity in humans may actually be a byproduct of selection for genes that slow development in order to get a larger smarter brain as a primary survival mechanism. Slowing development extends the windows of ‘‘super learning’’ by enhancing neuronal plasticity. Longer windows of time with high neuronal plasticity increase the chance that a neuron will make a connection from a learned experience which is essential for learning, memory and survival for humans. From the CDC Vital Statistics data and work pioneered by Thomas Perls it is clear that there are individuals that have genes for longer and healthier lifespan, but as a species the genetic variation is relatively tightly controlled (CDC NCHS, 2006; Perls, 2006). The idea that each age-related disease is independently influenced by a separate mechanism and set of genes has been dispelled by evidence that dietary (e.g. calorie restriction) and genetic (Table 5) interventions delay the onset and slow the progression of multiple diseases, and extend functional capacity proportional to the increase in maximum lifespan. Most age-related diseases (e.g. arteriosclerosis, cancer, Alzheimer’s disease, diabetes, osteoporosis, cataracts, etc.) share common risk factors such as excessive calorie
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intake, dietary saturated fats and sedentary lifestyle which suggests that they probably also share common cellular and molecular mechanisms. Aging is the loss of function and degeneration that eventually causes death. In the U.S., aging is the primary cause for the majority of loss of physical and mental performance, as well as, pain and disease. Prevention, which is a hallmark of Public Health, would require understanding the root cause/s of aging and then developing therapies to slow it down (Marshall, 2006).
Acknowledgement This work was supported by the National Institute on Aging Intramural Research Program.
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Review
Introduction: The adversities of aging Roy G. Cutler *, Mark P. Mattson Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA Received 5 February 2006; accepted 16 May 2006
Abstract The aging process is evolutionarily conserved and subject to quantitative modification by both genetic and environmental factors. Fundamental mechanisms of aging result in progressive deficits in the function of cells and organs, often leading to diseases that ultimately kill the organism such as cancers, cardiovascular disease and neurodegenerative disorders. Oxidative stress and damage to all of the major classes of molecules in cells are involved in aging and age-related diseases. The widely pursued approach of targeting disease-specific processes to develop therapeutic interventions has not had a major impact on healthspan. A more productive approach would be to target the fundamental mechanisms of aging throughout adult life so as to extend healthspan. Caloric restriction and regular exercise are two such approaches. Published by Elsevier Ireland Ltd. Keywords: Aging process; Oxidative stress; Healthspan
1. Aging is our #1 health problem Aging is the leading cause of disability and death in the United States and other developed countries. The 2003 CDC National Vital Statistics Report shows that about 85% of all deaths are caused by age-related diseases (Table 1; Fig. 1; CDC, National Vital Statistic Reports, 2006a). 2. The degenerative effects of aging are universal What we call aging is the noticeable loss of function and the onset of the degenerative diseases that is caused by the aging process. Many scientists and physicians define aging as * Corresponding author. E-mail address: [email protected] (R.G. Cutler). 1568-1637/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.arr.2006.05.002
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Table 1 The top 15 causes of death as reported by the CDC, National Vital Statistics for U.S. 2003 (raw data was obtained from CDC, National Vital Statistics Reports, 2006a) Cause of death Heart disease Cancer Stroke Pulmonary diseases Accidents Diabetes Pneumonia and influenza Alzheimer’s disease Nephritis (kidney) Septicemia (infection) Suicide Liver disease Hypertension Parkinson’s disease Homicide Other Total
Number of deaths in 2003 685089 556902 157689 126382 109277 74219 65163 63457 42453 34069 31484 27503 21940 17997 17732 416932 2448288
the loss of a cell/organ/organisms peak function that continues until its failure and death. In humans most physiological functions such as hearing, eyesight, taste, lung capacity, agility, immune response, adaptation to change, etc., reach peak ability between the ages of 11 and 20 years old. After that age there is a slow decline in performance as the degenerative process of aging begins (Bafitis and Sargent, 1977). The rate of the degenerative effects of aging is different for each cell/organ/organism due to genetics and environmental exposure. Most of us will not reach our species maximum lifespan potential due to the inheritance of genes that predisposes to an accelerated onset and/or progression of a
Fig. 1. Age is the greatest risk factor for developing degenerative diseases. The number of deaths from the top three causes in the U.S. for 2003 vs. age for the total population (raw data was obtained from CDC, National Vital Statistics Reports, 2006a).
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Table 2 Common age-related degenerative diseases and functional deficits (data obtained from Kohn, 1982; Maynard, 1966) List of common age-related degenerative process and functional deficits Loss of stem cell population Loss of hormone regulation Male patterned baldness Female menopause Sarcopenia (i.e. muscle weakness, frailty) Osteoporosis Graying hair Loss of insulin sensitivity Type II diabetes (insulin insensitive) Cancer Arteriosclerosis, heart disease, stroke Cataracts Hearing loss Incontinence Metabolic disturbances Osteoarthritis and rheumatoid arthritis Hypertension Loss of skin elasticity and collagen (i.e. wrinkles, liver spots, thinning) Retinal degenerative diseases (i.e. macular degeneration, retinitis pigmentosa) Lipofuscin and protein aggregates: ALS (SOD1), Alzheimer’s (Abeta), Parkinson’s (alpha-synucle in) Dementia Increase hair growth, density and root thickness in nose, ears, beard, chest, back, pubic, eye brows
particular age-related disease, and/or due to our environmental exposure to harmful agents that promote an age-related disease. If we are genetically and environmentally lucky, we can live to, or near, our species maximum lifespan potential, which is around 122 years old. However, the degenerative effect of aging is, in general, uniform for every cell/organ/ organism. Even though an elderly person has not died earlier from a genetic or environmentally induced weak link in their vital life processes, their bodies are still showing signs of the degenerative effects of aging. A good example to further illustrate that the degenerative effects of aging are universal is to look at a person that is over 100 years of age. They have not yet died of a particular disease, but they do have signs of degeneration and loss of function throughout their body such as loss of: hearing, hormone regulation, skin elasticity, taste, vision, memory, immune responsiveness, etc., that impairs their productivity and quality of life (Table 2; Fig. 2; Kohn, 1982; Maynard, 1966).
3. How much of an increase in quality of life and productivity can we expect from curing one ailment? It has been estimated that if we were able to completely eliminate and cure all forms of cancer the impact on healthspan and lifespan in the United States would only increase by an average of 2.3 years (National Center of Health Statistics. USPHS & U.S. Bureau of the Census, 1973; Tsai et al., 1978). The reason for this is that most people who suffer from major
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Fig. 2. (a) Self-accessed decrease of function and quality of life with age; (b) Clinically diagnosed disease or chronic health ailment causing limitation of activity (raw data for both figures were obtained from a CDC National Health Interview Survey conducted on 100,000 people across the U.S. from 2002–03(CDC, NCHS. Review Health, United States, 2005 Tables. http://www.cdc.gov/nchs/data/hus/hus05.pdf Health United States, Figs. 19 and 20). Surveys where sent to 358 primary sampling units (PSUs) drawn from approximately 1900 geographically defined PSUs that cover the 50 states and the District of Columbia.
killer diseases are over 65 years old and would soon be dying from another failing vital function (Table 3; Fig. 1). The elimination of fatal diseases such as coronary heart disease and cancer acts to increase the proportion of years with disability and healthcare costs because of the medical expenses during the added years of life. In contrast, not treating fatal diseases while eliminating disabling diseases like arthritis and osteoporosis acts to shorten lifespan, but with fewer years of disability (Nusselder et al., 1996; Bonneux et al., 1998).
4. Ages of peak performance and productivity The adverse effects of aging can clearly be seen in the quickly declining peak physical performance of athletes. For example, the average age of world record holding athletes
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Table 3 The potential gain in years of life expectancy if major causes of death were eliminated (raw data was obtained from USPHS, 1973; Tsai et al., 1978) Expectancy of Life gained at birth and age 65 years due to elimination of various causes of death Cause of death
Gain in expectancy of life (years) if cause was eliminated At birth
At 65 years old
Cardiovascular disease Heart disease Stroke Cancer Accidents (not motor vehicle) Motor vehicle accidents Influenza and pneumonia Infectious disease Diabetes
10.9 5.9 1.3 2.3 0.6 0.6 0.5 0.2 0.2
10.0 4.9 1.2 1.2 0.1 0.1 0.2 0.1 0.2
whose sport requires balance and explosive strength is 13–20 years old, whereas skilled sports such as tennis and golf peak at 24 and 31 years, respectively (Table 4; Kaga and Tanaka, 1980; Schulz and Curnow, 1988; Schulz et al., 1994; Baker et al., 2003; Anton et al., 2004; Nakamura et al., 1998). Animals that live in an environment where mortality from predation is high have evolved genetic programs for quick development and breeding that needs to be balanced with high fitness (e.g. gazelles on the plains of the African savanna being pursued by lions, tigers and cheetahs). The animals that are at the highest risk for being caught by a predator are the newborn and the middle-aged. You will rarely ever see any adverse signs of aging in either the predator or prey in these types of animal populations because top mental and Table 4 Peak ages for physiological performance as clinical norms for humans (gender and race averaged, then rounded to nearest whole value) Peak ages of physiological performance Hearing peaks at 5 years old Smell peaks at 10 years old Taste peaks at 10 years old Flexibility and balance peaks at 13 years old Muscle strength peaks at 18 years old Tissue repair peaks at 13 years old Short term memory peaks at 20 years old Creativity peaks at 4–6 years old Immune response peaks at 13 years old Lung capacity peaks at 20 years old Creativity data was highly variable and best expressed in a range. Flexibility, tissue repair capacity and immune response all peaked right before puberty, after which there was a sharp decline due to sex steroids. There was a notable difference between the peak lung capacity of female (17 years) and males (21 years) because of the 3.5year extension of bone growth in males. Peak height for females is 17 years and males is 21 years of age (Kaga and Tanaka, 1980; Schulz and Curnow, 1988; Schulz et al., 1994; Nakamura et al., 1998; Baker et al., 2003; Anton et al., 2004).
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physical performance (e.g. eye sight, hearing, explosive fast twitch muscle strength) are needed daily to survive (Ansved et al., 1991). A measurement of the age-related decline in functional performance as biomarkers of aging has been pioneered by sports physiologists such as Richard Hochschild for which he has developed the H-SCAN. This computer-based test connects with the provided headphones, lung peak flow meters, and other calibrated measuring devices to calculate the functional status of the subject and their estimated physiological age based on 12 tests (Hochschild, 1990). The tests include: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)
auditory reaction time; highest audible pitch; vibro-tactile sensitivity; visual reaction time; muscle movement time; lung: forced vital capacity; lung: forced expiratory volume, 1 s; decision reaction time; decision movement time; memory; alternate button tapping; visual accommodation (i.e. eye lens flexibility).
Pulmonary, cardio and exercise physiologists were the first to develop and standardize vital functional tests as biomarkers to determine a subject’s health status (e.g. tread mill stress test to determine VO2 max (maximum oxygen uptake) and maximum heart rate) to maximize an athlete’s performance (Fig. 3; http://www.americanheart.org/presenter.jhtml?identifier=4736; Cooper et al., 1992).
Fig. 3. Decrease of lung function (vital oxygen capacity, VO2 max) with age (raw data was obtained from Cooper et al., 1992), and decrease of heart function capacity (maximum heart rate) with age (raw data was obtained from the American Heart Organization website, http://www.americanheart.org/presenter.jhtml?identifier=4736).
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5. The evolution of lifespan ‘‘Nothing in biology makes sense except in the light of evolution’’: Theodosius Dobzhansky, geneticist (1900–1975). Most evolutionary scientists believe that humans evolved from the great apes with enhanced brain size, convolutions, and perpetual neoteny (i.e. curious, high ability to learn). These traits allowed humans to develop the key survival strategies of tool development, language, socialization, trans-generational information transfer, and migration to better adapt and control our environment. In order to get the largest brain through the mother’s birth canal human infants are born unusually immature and helpless relative to other species (Leigh and Park, 1998). One hypothesis of human evolution is that many of the genes that helped contribute to increased brain size also played roles in slowing fetal development rate. Humans are unique in that we are born with a very premature brain that keeps on growing after birth. A key difference between chimpanzee and human brains is that after birth the human brain continues to grow dramatically during the first postnatal year. About one-ninth of a newborn human baby’s weight is its brain. However, by the time a person reaches adulthood their brain only makes up 1/50th of their total body weight. In most species other than human, the number of neurons in their developing brain is fixed prior to birth. Human neonatal brain development and overall development seems to have been slowed down by changes in gene expression via an environmental selection for a larger adult brain. This slow down in development also has the advantage of extending key learning periods, or windows of opportunity, which gives children the exceptional abilities to learn language, tool usage and problem solving. These skills take time and often involve training during certain seasons, and necessitates a delay in sexual reproduction. We believe that during the evolution of man there was a strong environmental pressure for the selection of genes that slowed development rate by reducing the accumulation or signaling of key growth-regulating hormones. The lowering of such developmental hormones not only resulted in lengthening the time periods for brain growth and development, but also proportionally extended healthy years and maximum lifespan (Cutler and Semsei, 1989).
6. Are development and aging rates both determined by the same master genes and hormones? There is a strong correlation between a species maximum lifespan and its developmental rate, which suggests that these processes share a common mechanism that is species specific and genetically programmed (Cutler and Semsei, 1989; Bains et al., 1997). For example, the genetic code between chimpanzees and human is about 98% the same; however, the maximum potential lifespan for the chimpanzee is 56 years whereas for humans it is 122 years. This correlation suggests that the differences that determine the timing of developmental stages (e.g. puberty, brain maturation) and physiological aging rate (i.e. maximum lifespan potential) may be due to the expression of a very small number of genes. Work by de Magalha˜es and Sandberg
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Fig. 4. (a) Changes in synaptic plasticity and cognitive function with age; (b) changes in the total number of neurons and synapses across a lifespan (raw data was obtained from de Magalha˜es and Sandberg, 2005).
(2005) has shown that synaptic plasticity and cognitive function peak around the time of puberty and are maintained proportional to a species maximum lifespan potential. They propose that the same mechanisms that shape the adult phenotype continue at later ages contributing to cognitive dysfunction and eventually dementia (Fig. 4a and b). In general, the physiological aging rate of a cell/organ/organism/species can be defined by its maximum lifespan. In other words, physiological aging rate is directly related and relative to a species developmental rate and maximum lifespan potential. For example, one of the ways researchers have genetically selected for long-lived Drosophila melanogaster is to pick the ones that are last to sexually mature (Rose et al., 1992). Transgenic experiments also indicate that a reduction in certain growth factors can slow down developmental events while increasing health and extending maximum lifespan. Finally, a well-known characteristic of calorie-restricted mice/rats is the lower growth factors and delayed development, which includes reaching puberty (and the onset of menopause in females) later. The delay of developmental events by calorie restriction also occurs in monkeys and humans (Park et al., 1994; Holehan and Merry, 1985).
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Table 5 Genetically modified gene indicated by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB name), functional change (i.e. / double chromosome knockout, ++/++ over expression of gene) and note on catalytic function Gene changed
Extension of maximum life span (%)
Species
p66shc / (apoptosis, phenoptosis) PROP1 / (GH, prolactin orTSH) GHR/BP / (GH receptor binding protein)
30 50 50
Mouse (Migliaccio et al., 1999) Mouse (Bartke et al., 1998) Mouse (Coschigano et al., 2000)
Cu/ZnSOD ++/++ (in motorneurons) MnSOD ++/++ (in motorneurons) mth / (putative G-protein-coupled receptor) indy / (sodium dicarboxylate cotransporter)
40 30 35
Drosophila (Parkes et al., 1998) Drosophila (Phillips et al., 2000) Drosophila (Schmidt et al., 2000)
45
Drosophila (Rogia et al., 2000)
age-1 / (PI3 kinase homologue) daf 2 / (insulin receptor homologue) clk-1 / (CoQ biosynthesis homologue) spe-10 / (unknown) spe-26 / (unknown) old-1 / (putative receptor tyrosine kinase)
65 100
C. elegans (Johnson et al., 2000) C. elegans (Kenyon et al., 1993)
40
C. elegans (Wong et al., 1995)
40 65 65
C. elegans (Cypser and Johnson, 1999) C. elegans (Lithgow et al., 1995) C. elegans (Rikke et al., 2000)
7. Evidence that individual genes regulate lifespan Humans live about two times longer than our nearest relatives, the chimpanzee and bonobo. Humans also have an unusually long span of healthy and productive years of life relative to most other species. So what makes humans live long and healthy lives? Research indicates the existence of ‘‘longevity determinant genes’’ (Cutler et al., 2005; Vijg and Suh, 2005). Genetic analyses of human lineages with exceptional longevity have honed in on specific regions of the genome (e.g. chromosome 4) (Perls and Terry, 2003). However, only a few specific longevity-related genes have been identified. For example, a recent study of Ashkenazi Jewish centenarians in which 36 different genes related to cardiovascular disease were analyzed demonstrated a strong correlation of a polymorphism in the apolipoprotein C3 gene promoter with longevity (Atzmon et al., 2006). While progress in identifying genes that regulate longevity in humans has been slow, numerous such genes have been identified in lower organisms. The genes listed in Table 5 have been shown to affect the maximum lifespan of mice, flies and, providing evidence that individual genes can have a big impact on increasing the lifespan and health span of a species. What most of these genes have in common is that they relate to oxidative stress and developmental growth factors such as insulin and IGF-1. Oxidative damage has been shown to play a key role in the onset and progression of age-related diseases, and therapies to reduce oxidative stress often help to slow down the disease process and maintain good health.
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8. Can aging be slowed? Calorie restriction can increase the lifespan of rodents by up to 40%, which is accompanied by a proportional extension of healthspan (Weindruch and Sohal, 1997). Calorie restriction has been shown to slow the onset and progression of age-related degeneration of tissues throughout the body including collagen cross linking, accumulation of lipofuscin, lipid droplets, sarcopenia, cataracts, cognitive decline, kidney disease, arthritis and cancer. The magnitude of the life-extending effect of calorie restriction depends upon the energy intake of the control group and the amount by which calories are reduced below the control level. In most studies of mice and rats the control group are fed ad libitum and equivalent to overfed obese humans. However, if nutritional requirements are maintained, then the progressive reduction in calorie intake continues to extend lifespan until near the point of starvation. Studies of non-human primates (Roth et al., 2004) and of humans (Heilbronn et al., 2006) suggest that calorie restriction will also extend lifespan in humans. Two major hypotheses of the root cause of aging: (1) Accumulation of damaged molecules—which includes the free radical hypothesis of aging, was first developed by Harman in 1957 and today is the most popular hypothesis among gerontologists (Harman and Harman, 2003). Examples of oxidative damage include oxidized proteins, protein aggregates (e.g. amyloid beta peptide in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease), lipofuscin, lipid peroxides (e.g. 4hydroxy-nonenal, 8-epi-prostaglandin F2alpha), oxidized DNA adducts (e.g. 8hydroxy-2-deoxy-guanosine) and glycation products (Terman, 2001). This hypothesis also includes the idea that the accumulation of (oxidatively induced) DNA mutations results in aberrant gene expression, defective proteins and increased incidence of cancer and cell death. However, recent data in mice indicate that the qualitative and quantitative nature of DNA damage and repair does not change significantly with age (Hill et al., 2005). However, there is considerable evidence supporting a role for the accumulation of mitochondrial DNA deletions with aging and oxidative stress, particularly in postmitotic cells such as neurons and myocytes (Kraytsberg et al., 2006). (2) Antagonistic pleiotropy—first developed by G.C. Williams in 1957, which states that a gene or gene product that is responsible for positive effects when young, later causes the detrimental effects of aging (Rose and Charlesworth, 1980). Since most species in the wild are killed by environmental hazards before they become old, negative pleiotropic genes would not be evolutionarily selected for. One example of a possible antagonistic pleiotropy mechanism is the accumulation of sterols and steroids to toxic levels during aging (e.g. cholesterol in cardiovascular foam cells, estrogens in precancerous breast and prostate cells) (Huber et al., 2002; Bellosta et al., 2000).
9. What can we do about aging now? (1) Limit calories to maintain a healthy mass index (BMI). Many health experts would also suggest fasting with plenty of water. The length and frequency of fasting should be individualized to a regimen makes you feel healthy.
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(2) Exercise—the current Department of Health and Human Services, USDA recommendation is 60 min of exercise three to four times per week (USDA, Dietary Guidelines, 2005). Exercising in the morning before eating is a popular way to rev-up the metabolic system, increasing fat catabolism and decreasing glucose levels similar to that which occurs during a 24 h fast. In fact, studies have shown that 20 min of morning (or 4 h fast) exercise has the same fat burning effect as 60 min after food intake (Bergman and Brooks, 1999; McCarty, 1995). Exercise has also been shown be a stressor that acts to induce phase II detoxification, a mechanism much like that suggested for the beneficial dietary effects of phytochemicals in fruits and vegetables (Duncan et al., 1997). (3) Eat fruits and vegetables—the USDA recommends eating five servings of fruits and vegetables per day (USDA, Dietary Guidelines, 2005). The health benefits of fruits and vegetables are not the same; there are some that have been classified by many as ‘‘super foods’’. These include the brassica, or cruciferous, family of vegetables, which includes cabbage, broccoli and broccoli sprouts (which contain sulforaphane), cauliflower, bok choy and horseradish (which contain 6-methylsulfinyhexyl isothiocyanate). Also on the list of ‘‘super foods’’ are brussel sprouts, spinach, kale, carrots and blueberries. Epidemiology studies have shown that people who frequently eat broccoli had much lower incidences of many types of cancer and Alzheimer’s disease (http://www.alzinfo.org/news/NewsArticle7-29-2004-11-38-AM.aspx; http:// www.alzinfo.org/news/NewsArticle8-18-2005-1-35-PM.aspx; Michaud et al., 1999). The mechanism by which broccoli benefits health does not seem to be by the antioxidants as previously thought, but by the natural poisons (i.e. insecticides) used by the plant to ward off insects. These compounds like sulforaphane in broccoli and terpenoids in citrus oils activate the phase II pathway that conjugates the poison and removes it from the body. The healthy aspect of this process is that while getting rid of the food poisons the revved-up phase II conjugation mechanism also cleans up other harmful metabolic byproducts like oxidized steroids and lipid peroxides. Phenolic antioxidants like tocopherol (i.e. Vitamin E), carotenoids, and many dietary spices (e.g. curcumin, black pepper, brown mustard), also activate this pathway and so the biggest benefit in dietary phytochemicals may not be in trapping free radicals but in activating the phase II conjugation mechanism (Gao and Talalay, 2004). (4) Clean environment—limit chronic exposure to toxins and carcinogens like tobacco smoke, alcohol and radon. (5) Optimize stress—as with most biological processes, the amount of stress, rest and sleep required for optimal health follows a bell curve; too little or too much are bad for long term health. Studies have shown that the longest lived people get between 7 and 8 h of sleep per night and subject themselves to moderate daily de-stressors including exercise and social interactions (Kripke et al., 2002; Patel et al., 2004).
10. How would slowing aging affect our population? Many people believe that by slowing the degenerative aging process we would have too many physiologically old people, a social security crisis and in general more problems than it is worth. In reality, we would have more physiologically younger people who have a
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higher productivity because of an increased number of years working at peak physiological performance. Providing that the birth rate is low, the end result would be a higher percentage of the population would stay in the work force longer. People would have the ability and drive to work for many years longer, personal income and savings would increase and the overall national economy would flourish. As America and most industrial nations working population ages, the percent of disabled and retired people go up which puts an economic strain on the current working population and governments. On its current path, the United States Medicare program is estimated to go bankrupt by the year 2019 and Social Security by 2042 (Gundling, 2001; CEA, 2005). Trying to cure or treat the symptoms of each age-related disease separately as if they were unrelated to one another has not had a major impact on quality of life and productivity (Tables 2 and 3). The current piece meal approach to healthcare also seems to be exacerbating our economic problems by utilizing expensive temporary patches (e.g. drugs and surgery) that result in a minor slowing of disease processes and prolongation of the period of morbidity. This strategy usually does not result in returning people back to the workforce and is not cost effective for the individual, retirement programs, health care programs or the government. However, there is little incentive to institute anti-aging interventions that would increase healthspan because the current system of geriatric medicine is a major profitable market for physicians and pharmaceutical companies.
11. What about the economics of slowing aging? Overpopulation could be a potential problem because of the extension of childbearing years. However, one factor that may play a big roll in circumventing this potential problem is that the majority of the people who are interested in voluntarily enhancing their health and longevity are usually well educated and tend to have small families (Marshall and Marshall, 1982). Many developed nations populations have been shrinking due to having less children. The number of people 65 years and older in many developed countries such as Italy, Germany and Japan is currently up to 20%, and estimated to be near 35% by 2050. The elderly dependency ratio in Japan is expected to go up to 71 retired per 100 working age people by 2050 compared to the current ratio of 54.3/100 (US 2006 elderly dependency ratio is 35.3) (http://www.census.gov/ipc/www/idbagg.html) (Ishibashi, 1998). The decline in the working population is expected to cause age-related economic recessions throughout the world, which will put greater pressure on employee efficiency, automation and demand for energy (e.g. petroleum). The cost of decreased job performance do to degenerative aging is substantial. This can particularly be seen in the short career spans of athletes (Young and Starkes, 2005). Just a minor weakening of eyesight, hearing or slower reaction time can cost athletes the game and increases risk of injury (Schulz et al., 1994; Barry and McGuire, 1996). The effects of aging on the functional performance in the US workforce can be seen in the changes in productivity and working hours; note that peak employment productivity closely follows the general peaks of physiological functions during our lifespan (Fig. 5; CDC National Center for Health Statistics, 2006b). From 1950 to 2004 healthcare expenditures in the United State rose 300%, while the population only increased by 200% (http://www.cdc.gov/nchs/data/hus/hus05.pdf#091).
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Fig. 5. (a) Age of peak employment productivity (hours worked/week) and age of peak physiological function as measured by vital lung capacity; (b) average number of deaths per 100k employed workers during 1994–2001 (raw data was obtained from CDC United States Health 2005 report. www.cdc.gov/nchs/data/hus/hus05.pdf).
This increase was largely due to the 9% increase in our aging population. Over 87% of healthcare and pharmaceutical costs come from people over 45 years old (http:// www.cdc.gov/nchs/data/hus/hus05.pdf#091). It is estimated that by 2050 the population of people 65 years and over will rise 240%, from 7.6% (2004) to 18.3% (2050). Unless changes are made the predicted 2050 healthcare expenditure will be about 25% of the gross national product (CDC National Center for Health Statistics, 2005).
12. What about our quality of life? Increasing healthy years of life acts to increase our environmental hazards, which could hypothetically be extended to a point where we are more likely to die from an accident rather than wasting away in a nursing home. Extending the years of peak function,
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performance, and productivity will not only add to our own personal enjoyment of life but will also significantly add to the wealth of our economy.
13. Feasible goals A few gerontologists like Robert Butler have set a target of increasing average healthspan by 7 years. This goal was chosen because the exponential rise of onset and progression of age-related diseases doubles approximately every 7 years. Extending our lifespan by 7 years would result in cutting in half the incidence and prevalence of frailty, disability and risk of major causes of morbidity and mortality across the board (Butler and Brody, 1995; Butler, 2004).
14. A milligram of prevention is worth a kilogram of cure: a call to action By the time a patient is symptomatic and clinically diagnosed with an age-related disease the damage has already been done. All age-related diseases progress slowly such that the patient has usually experienced years of progressive loss of function, loss of work performance and quality of life. Once the damage is done going back to try to repair it is in most cases currently impossible. Recently, gerontologists have been focusing their research program goals toward ‘‘successful aging’’, ‘‘healthy aging’’ or ‘‘aging gracefully’’. We feel that this terminology is off the mark and may even misdirect research efforts away from trying to find the root cause of the problem to just reacting to the many symptoms related to aging. Instead, the answer to increasing healthspan lies in prevention by understanding the root causes of aging and holistically slowing down the aging process thereby delaying the loss of performance, degeneration and disease. The result would be an increase of healthy and productive years. Each species has a tightly controlled development and maturation rate that fits with their life cycle. The driving force for unusual longevity in humans may actually be a byproduct of selection for genes that slow development in order to get a larger smarter brain as a primary survival mechanism. Slowing development extends the windows of ‘‘super learning’’ by enhancing neuronal plasticity. Longer windows of time with high neuronal plasticity increase the chance that a neuron will make a connection from a learned experience which is essential for learning, memory and survival for humans. From the CDC Vital Statistics data and work pioneered by Thomas Perls it is clear that there are individuals that have genes for longer and healthier lifespan, but as a species the genetic variation is relatively tightly controlled (CDC NCHS, 2006; Perls, 2006). The idea that each age-related disease is independently influenced by a separate mechanism and set of genes has been dispelled by evidence that dietary (e.g. calorie restriction) and genetic (Table 5) interventions delay the onset and slow the progression of multiple diseases, and extend functional capacity proportional to the increase in maximum lifespan. Most age-related diseases (e.g. arteriosclerosis, cancer, Alzheimer’s disease, diabetes, osteoporosis, cataracts, etc.) share common risk factors such as excessive calorie
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intake, dietary saturated fats and sedentary lifestyle which suggests that they probably also share common cellular and molecular mechanisms. Aging is the loss of function and degeneration that eventually causes death. In the U.S., aging is the primary cause for the majority of loss of physical and mental performance, as well as, pain and disease. Prevention, which is a hallmark of Public Health, would require understanding the root cause/s of aging and then developing therapies to slow it down (Marshall, 2006).
Acknowledgement This work was supported by the National Institute on Aging Intramural Research Program.
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